Pluripotent hematopoietic stem cells have emerged as a heterogeneous population of cells that differ in phenotype and repopulation kinetics. Stem cells in vitro and in vivo are dependent upon stromal cells for their proliferation and differentiation. Thus, stromal cells can be viewed as tools to analyze the physiological conditions that regulate stem cells. Stromal cell lines that support stem cells are infrequent, which supports the interpretation that stromal cells create distinct niches that regulate stem cell development. A model of stem cell maintenance is presented that predicts that stromal cell-bound molecules protect stem cells from differentiation. The stroma compartment is highly adaptable and can change its function in response to external stimuli. Thus, it is tempting to speculate that the stroma acts as a translator of peripheral signals for stem cells.